The present invention relates to a method of treating malaria comprising administering an effective amount of an FPT inhibitor to a patient in need of such treatment alone or in combination with an additional antimalarial agent and/or agent for reversing antimalarial resistance.
The present invention also relates to novel Farnesyl Protein Transferase inhibitors, methods of preparing such inhibitors, compositions containing such inhibitors and methods of using such inhibitors in the treatment of malaria.
Malaria is one of the most widespread infectious diseases in the world infecting over 200 million people of which, it has been estimated, 1-2 million die from the disease per year.
Malaria is a disease caused by a parasite transmitted by the bite of an infected female Anopheles mosquito. When an infecting sporozoite parasite enters the bloodstream it rapidly infects both liver and red blood cells and differentiates into merozoites. Asexual reproduction of the merozoite within erythrocytes results in the rupture and subsequent reinfection of other red blood cells. This cyclic process results in clinical symptoms of headaches, sweating, vomiting, malaise, delirium and acute fever and may be fatal if not treated.
There are four main species, which infect humans, Plasmodium vivax, Plasmodium malariae, Plasmodium ovale, and Plasmodium faliciparum. Several anitmalarial drugs have been developed to treat the disease. Chloroquine and quinine have been used widely for over forty years because they have been exceptionally safe, inexpensive and effective drugs for treating the disease. Recently, however, chloroquine- and quinine-resistant strains of P. faliciparum have developed and are causing high levels of mortality. In an effort to identify a new and more effective method for treating malaria, Chakrabarti et. al., have studied the use of inhibitors of prenyl transferases from the malaria parasite, Plasmodium falciparum, in an effort to identify a method for treating malaria, see Chakrabarti, et al., Molecular and Biochemical Parasitology (1998) 94, 175-184.
In view of the need to find new treatments of malaria, those skilled in the art would welcome an effective method for the treatment of malaria. The present invention provides such a method utilizing inhibitors of Plasmodium falciparum protein prenyl transferases.
This invention provides a method of treating and/or preventing malaria comprising administering to a patient, in need of such treatment, an effective amount (e.g., a therapeutically effective amount, or an amount to inhibit malaria) of a Farnesyl Protein Transferase inhibitor selected from Compounds 1-26 described below.
This invention also provides novel compounds (i.e., novel FPT inhibitors) selected from the compounds: 14, or 16-23 described below.
As used herein, the following terms are used as defined below unless otherwise indicated:
MH+-represents the molecular ion plus hydrogen of the molecule in the mass spectrum;
BOC-represents-t-BOC-represents-tert-butyloxycarbonyl;
CBZ-represents xe2x80x94C(O)OCH2C6H5 (i.e., benzyloxycarbonyl);
CH3CN-represents-acetonitrile;
CDCl3-represents-deuterated chloroform
CH2Cl2-represents dichloromethane;
CIMS-represents chemical ionization mass spectroscopy;
DEA-represents diethyl amine;
DMSO-represents dimethyl sulfoxide
DMF-represents N,N-dimethylformamide;
EI-represents electron ionization spectroscopy;
Et-represents ethyl;
Et2O-represents diethyl ether;
EtOAc-represents ethyl acetate;
EtOH-represents ethanol;
HCl-represents hydrochloric acid
IPA-represents isopropanol;
LAH-represents lithium aluminum hydride;
LCMS-represents liquid chromatography mass spectroscopy;
Me-represents methyl;
MeOH-represents methanol;
MgSO4-represents magnesium sulfate;
MS-represents mass spectroscopy;
FAB-represents FABMS which represents fast atom bombardment mass spectroscopy;
HRMS-represents high resolution mass spectroscopy;
NaOH-represents sodium hydroxide;
Na2SO4-represents sodium sulfate;
NaHCO3-represents sodium bicarbonate;
NH4OH-represents amonium hydroxide;
NOE-represents nuclear Overhauser effect;
NMR-represents nuclear magnetic resonance spectroscopy;
NMM-represents N-methylmorpholine;
p-TosCl-represents p-toluenesulfonyl chloride;
P2O5-represents phosphorous pentoxide;
Pr-represents propyl;
Et3N-represents TEA which represents triethylamine;
t-BUTYL-represents xe2x80x94Cxe2x80x94(CH3)3;
TFA-represents trifluoroacetic acid;
THF-represents tetrahydrofuran;
TLC-represents thin layer chromatography;
FPT-represents Farnesyl Protein Transferase
One skilled in the art will appreciate that the positions of the Nitrogen atoms around the imidazole portion of the compounds described below are: 
The FPT inhibitors useful in the claimed invention are:
Preferably the compound (3) 
is used in the methods of this application.
The novel FPT inhibitory compounds are:
In another embodiment, this invention provides a method of treating malaria, wherein, the compounds 1-26 described herein above, are administered in combination with an additional antimalarial agent and/or an antimalarial resistance reversing agent. In general, additional antimalarial agents and/or antimalarial resistance reversing agents are ones known in the art to treat or prevent malaria, such as, for example quinolines (e.g. Chloroquine), folic acid antagonists (e.g. pyrimethamine), sulfonamides (e.g. sulfadiazine), antibiotics (e.g. tetracycline) and/or inhibitors of multidrug resistance (e.g. tetrandrine).
In general, in combination with, means, the additional antimalarial agents and/or antimalarial resistance reversing agents may be administered prior to, concurrent with, or subsequent to, the administration of a therapeutically effective amount of a compound selected from 1-26.
Compounds useful in this invention are exemplified by the following examples, which should not be construed to limit the scope of the disclosure.